Abstract

Introduction: Mutations in cardiac myosin binding protein-C (MYBPC3), the most common genetic cause of hypertrophic cardiomyopathy (HCM), have been reported to cause a comparatively benign and late-onset form of the disease with incomplete penetrance. Based upon selected families with small numbers of mutations, these early reports may be misleading however. This study aimed to redefine the clinical characteristics of HCM related to MYBPC3 by evaluating a large cohort of unselected patients and their families, in whom an MYBPC3 mutation had been identified.
Methods: Index cases and their families underwent history, physical examination, electrocardiogram (ECG), transthoracic echocardiography, ambulatory ECG monitoring, metabolic exercise testing and mutation analysis. Long-term follow up data was collected where available.
Results: 44 MYBPC3 mutations were identified in 59 index cases. 26 of 59 (44%) were missense with 11 (19%) insertions/deletions, 11 (19%) intronic, and 5 (8%) nonsense mutations. A further 6 (10%) had complex genetic status with two different sequence variations identified. Nine families shared the R502W missense mutation and haplotype analysis confirmed a common founder, the first to be described in a UK cohort. A further 111 mutation carriers were identified, of which 39 were clinically affected - disease penetrance was therefore incomplete (58%) and related to age and gender but not mutation type. Mean age at diagnosis was 40.1 +/- 15.9 years with a wide range (5-76); 91.8% of affected mutation carriers were diagnosed over the age of 20 years. Most had asymmetric septal hypertrophy (86.4%) and mean maximal wall thickness was 20 +/- 5.8mm. Families sharing identical mutations showed significant variability in disease penetrance, age at diagnosis and risk of sudden death, suggesting that modifying factors play a significant role in disease development. No clinically useful markers of early disease expression were apparent from tissue Doppler studies in unaffected genotyped relatives. During long term follow up (mean 7.9 +/- 4.5 years) 1 individual developed hypertrophy as an adult, 5 individuals died (3 suddenly) and overall survival was 94%.
Discussion: The broad spectrum of mutations, disease severity and natural history of disease suggests that earlier reports of late-onset, benign disease related to MYBPC3 mutations were premature. In this study disease expression is broadly similar to non-genotyped HCM cohorts with disease severity ranging from mild to severe, risk of sudden death ranging from low to high and clinical disease being diagnosed in all decades of life. Such variance is not adequately explained by the sarcomeric protein gene or specific mutation per se and other genetic and environmental factors influence disease penetrance, severity and prognosis. The next generation of genotype-phenotype studies require a shift in focus from single gene analysis to include other genetic and environmental variables and an international collaborative database is recommended.